Cytogenetic and Genome Research

Novel Insights from Clinical Practice

Iwata-Otsubo A. · Darr K.R. · Torres-Martinez W. · Hodge J.C.

Author affiliations

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

Log in to MyKarger to check if you already have access to this content.

Buy FullText & PDF Unlimited re-access via MyKarger Unrestricted printing, no saving restrictions for personal use read more

CHF 38.00 *
EUR 35.00 *
USD 39.00 *

Select

KAB

Buy a Karger Article Bundle (KAB) and profit from a discount!

If you would like to redeem your KAB credit, please log in.

Save over 20% compared to the individual article price.

Learn more

Access via DeepDyve Unlimited fulltext viewing of this article Organize, annotate And mark up articles Printing And downloading restrictions apply

Select

Subscribe Access to all articles of the subscribed year(s) guaranteed for 5 years Unlimited re-access via Subscriber Login or MyKarger Unrestricted printing, no saving restrictions for personal use read more

Subcription rates

Select

* The final prices may differ from the prices shown due to specifics of VAT rules.

Article / Publication Details

First-Page Preview

Received: April 04, 2022
Accepted: August 18, 2022
Published online: December 14, 2022

Number of Print Pages: 7
Number of Figures: 3
Number of Tables: 1

ISSN: 1424-8581 (Print)
eISSN: 1424-859X (Online)

For additional information: https://www.karger.com/CGR

Abstract

Brachydactyly mental retardation syndrome (BDMR) typically results from large deletions (>2–9 Mb) in distal 2q37. Haploinsufficiency of HDAC4 with incomplete penetrance has been proposed as the primary genetic cause of BDMR. To date, pure 2q37 deletions distal to HDAC4 were reported only in a limited number of individuals who share a subset of the clinical manifestations seen in cases with 2q37 deletions encompassing HDAC4. Here, we present a 4-year-old African American male who carries the smallest established 2q37.3 deletion distal to HDAC4 (827.1 kb; 16 OMIM genes). His clinical features that overlap with BDMR phenotypes include expressive-receptive language delay, behavioral issues, mild facial dysmorphism such as frontal bossing, and bilateral 5th finger brachydactyly and clinodactyly. The deletion was inherited from his mother with a history of learning difficulties and similar facial dysmorphism. This case provides important genotype-phenotype correlation information and suggests a 2q37 region distal to HDAC4 encompassing the HDLBP gene may contribute to a subset of clinical features overlapping with those seen in individuals with BDMR.

© 2022 S. Karger AG, Basel

References Aldred MA, Sanford ROC, Thomas NS, Barrow MA, Wilson LC, Brueton LA, et al. Molecular analysis of 20 patients with 2q37.3 monosomy: Definition of minimum deletion intervals for key phenotypes. J Med Genet. 2004;41(6):433–9. Falk RE, Casas KA. Chromosome 2q37 Deletion: Clinical and molecular aspects. Am J Med Genet C Semin Med Genet. 2007;145C(4):357–71. Felder B, Radlwimmer B, Benner A, Mincheva A, Tödt G, Beyer KS, et al. FARP2, HDLBP and PASK are downregulated in a patient with autism and 2q37.3 deletion syndrome. Am J Med Genet A. 2009;149A(5):952–9. Imitola J, Khurana DS, Teplyuk NM, Zucker M, Jethva R, Legido A, et al. A novel 2q37 microdeletion containing human neural progenitors genes including STK25 results in severe developmental delay, epilepsy, and microcephaly. Am J Med Genet A. 2015;167A(11):2808–16. Jean-Marçais N, Decamp M, Gérard M, Ribault V, Andrieux J, Kottler ML, et al. The first familial case of inherited 2q37.3 interstitial deletion with isolated skeletal abnormalities including brachydactyly type E and short stature. Am J Med Genet A. 2015;167A(1):185–9. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–43. Kleinjan DA, van Heyningen V. Long-range control of gene expression: Emerging mechanisms and disruption in disease. Am J Hum Genet. 2005;76(1):8–32. Le TN, Williams SR, Alaimo JT, Elsea SH. Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports HDAC4 as the primary genetic contributor. Am J Med Genet A. 2019;179(5):782–91. Leroy C, Landais E, Briault S, David A, Tassy O, Gruchy N, et al. The 2q37-deletion syndrome: An update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients. Eur J Med Genet. 2013;21(6):602–12. Moretti PN, Figueiredo ACV., Saliba A, Versiani BR, Oliveira SF, Pic-Taylor A, et al. Genotype and phenotype correlation in a family with a 2q37 deletion downstream of HDAC4. Am J Med Genet A. 2020;182(8):1861–4. Ogura K, Takeshita K, Arakawa C, Shimojima K, Yamamoto T. Neuropsychological profiles of patients with 2q37.3 deletion associated with developmental dyspraxia. Am J Med Genet B Neuropsychiatr Genet. 2014;165B(8):684–90. O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485(7397):246–50. Satterstrom FK, Kosmicki JA, Wang J, Breen MS, de Rubeis S, An JY, et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell. 2020;180(3):568–584.e23. Seaby EG, Smedley D, Taylor Tavares AL, Brittain H, van Jaarsveld RH, Baralle D, et al. A gene-to-patient approach uplifts novel disease gene discovery and identifies 18 putative novel disease genes. Genet Med. 2022;24(8):1697–707. Takata A, Miyake N, Tsurusaki Y, Fukai R, Miyatake S, Koshimizu E, et al. Integrative analyses of de novo mutations provide deeper biological insights into autism spectrum disorder. Cell Rep. 2018;22(3):734–47. Temtamy SA, McKusick VA. The genetics of hand malformations. Birth Defects Orig Artic Ser. 1978;14:187–299. Villavicencio-Lorini P, Klopocki E, Trimborn M, Koll R, Mundlos S, Horn D. Phenotypic variant of brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4. Eur J Med Genet. 2013;21(7):743–8. Wheeler PG, Huang D, Dai Z. Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals. Am J Med Genet A. 2014;164A(7):1826–9. Williams KD, Blangero J, Cottom CR, Lawrence S, Choh AC, Czerwinski SA, et al. Heritability of brachydactyly type A3 in children, adolescents, and young adults from an endogamous population in eastern Nepal. Hum Biol. 2007;79(6):609–22. Williams SR, Aldred MA, der Kaloustian VM, Halal F, Gowans G, McLeod DR, et al. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am J Hum Genet. 2010a;87(2):219–28. Williams SR, Girirajan S, Tegay D, Nowak N, Hatchwell E, Elsea SH. Array comparative genomic hybridisation of 52 subjects with a Smith-Magenis-like phenotype: identification of dosage sensitive loci also associated with schizophrenia, autism, and developmental delay. J Med Genet. 2010b;47(4):223–9. Article / Publication Details

First-Page Preview

Received: April 04, 2022
Accepted: August 18, 2022
Published online: December 14, 2022

Number of Print Pages: 7
Number of Figures: 3
Number of Tables: 1

ISSN: 1424-8581 (Print)
eISSN: 1424-859X (Online)

For additional information: https://www.karger.com/CGR

Copyright / Drug Dosage / Disclaimer Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.